Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 25 April 2008:
Vol. 320. no. 5875, pp. 524 - 527
DOI: 10.1126/science.1155085
Prev | Table of Contents | Next

Reports

Plastin 3 Is a Protective Modifier of Autosomal Recessive Spinal Muscular Atrophy

Gabriela E. Oprea,1,2,3 Sandra Kröber,1,2 Michelle L. McWhorter,4 Wilfried Rossoll,5 Stefan Müller,3 Michael Krawczak,6 Gary J. Bassell,5 Christine E. Beattie,4 Brunhilde Wirth1,2,3*

Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.

1 Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
2 Institute of Genetics, University of Cologne, 50931 Cologne, Germany.
3 Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
4 Centre for Molecular Neurobiology and Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
5 Emory University School of Medicine, Department of Cell Biology, Atlanta, GA 30322, USA.
6 Institute of Medical Informatics and Statistics, Christian-Albrechts University of Kiel, 24105 Kiel, Germany.

* To whom correspondence should be addressed. E-mail: brunhilde.wirth{at}uk-koeln.de

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Pre-symptomatic development of lower motor neuron connectivity in a mouse model of severe spinal muscular atrophy.
L. M. Murray, S. Lee, D. Baumer, S. H. Parson, K. Talbot, and T. H. Gillingwater (2009)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate.
L. Garbes, M. Riessland, I. Holker, R. Heller, J. Hauke, C. Trankle, R. Coras, I. Blumcke, E. Hahnen, and B. Wirth (2009)
Hum. Mol. Genet. 18, 3645-3658
   Abstract »    Full Text »    PDF »
Zebrafish survival motor neuron mutants exhibit presynaptic neuromuscular junction defects.
K.-L. Boon, S. Xiao, M. L. McWhorter, T. Donn, E. Wolf-Saxon, M. T. Bohnsack, C. B. Moens, and C. E. Beattie (2009)
Hum. Mol. Genet. 18, 3615-3625
   Abstract »    Full Text »    PDF »
Differences in SMN1 allele frequencies among ethnic groups within North America.
B C Hendrickson, C Donohoe, V R Akmaev, E A Sugarman, P Labrousse, L Boguslavskiy, K Flynn, E M Rohlfs, A Walker, B Allitto, et al. (2009)
J. Med. Genet. 46, 641-644
   Abstract »    Full Text »    PDF »
A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice.
E. Workman, L. Saieva, T. L. Carrel, T. O. Crawford, D. Liu, C. Lutz, C. E. Beattie, L. Pellizzoni, and A. H.M. Burghes (2009)
Hum. Mol. Genet. 18, 2215-2229
   Abstract »    Full Text »    PDF »
Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy.
F. F. Rose Jr, V. B. Mattis, H. Rindt, and C. L. Lorson (2009)
Hum. Mol. Genet. 18, 997-1005
   Abstract »    Full Text »    PDF »
Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation.
K. Meyer, J. Marquis, J. Trub, R. Nlend Nlend, S. Verp, M.-D. Ruepp, H. Imboden, I. Barde, D. Trono, and D. Schumperli (2009)
Hum. Mol. Genet. 18, 546-555
   Abstract »    Full Text »    PDF »
Impaired Synaptic Vesicle Release and Immaturity of Neuromuscular Junctions in Spinal Muscular Atrophy Mice.
L. Kong, X. Wang, D. W. Choe, M. Polley, B. G. Burnett, M. Bosch-Marce, J. W. Griffin, M. M. Rich, and C. J. Sumner (2009)
J. Neurosci. 29, 842-851
   Abstract »    Full Text »    PDF »
Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition.
J. Hauke, M. Riessland, S. Lunke, I. Y. Eyupoglu, I. Blumcke, A. El-Osta, B. Wirth, and E. Hahnen (2009)
Hum. Mol. Genet. 18, 304-317
   Abstract »    Full Text »    PDF »
SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain.
M. P. Walker, T.K. Rajendra, L. Saieva, J. L. Fuentes, L. Pellizzoni, and A. G. Matera (2008)
Hum. Mol. Genet. 17, 3399-3410
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)